Method for preparation of fluoro, chloro and fluorochloro alkylated compounds by homogeneous catalysis

ABSTRACT

The invention discloses a method for preparations of fluoro, chloro and fluorochloro alkylated compounds by homogeneous Pd catalyzed fluoro, chloro and fluorochloro alkylation with fluoro, chloro and fluorochloroalkyl halides in the presence of di(1-adamantyl)-adamantyl-n-butylphosphine and in the presence of 2,2,6,6-tetramethylpiperdine 1-oxyl.

RELATED APPLICATIONS

This application is the national stage entry of International PatentApplication No. PCT/EP2015/075763 having a filing date of Nov. 5, 2015,which claims the filing benefit of U.S. Provisional Application No.62/076,618, having a filing date of Nov. 7, 2014, European PatentApplication No. 14192280.7, having a filing date of Nov. 7, 2014,European Patent Application No. 15181003.3, having a filing date of Aug.13, 2015, and European Patent Application No. 15181019.9, having afiling date of Aug. 14, 2015, all of which are incorporated herein byreference in their entirety.

FIELD OF THE INVENTION

The invention discloses a method for preparation of fluoro, chloro andfluorochloro alkylated compounds by homogeneous Pd catalyzed fluoro,chloro and fluorochloro alkylation with fluoro, chloro and fluorochloroalkyl halides in the presence of di(1-adamantyl)-n-butylphosphine and inthe presence of 2,2,6,6-tetramethylpiperidine 1-oxyl.

BACKGROUND OF THE INVENTION

Organofluorine chemistry plays an important role in medicinal,agricultural, and material sciences and fields. Fluoroalkyl groups havestrong effects such as high stability and lipophilicity, in addition,longer fluoroalkyl groups have high water and oil resistance and lowfricition.

Loy, R. N., et al., Organic Letters 2011, 13, 2548-2551, disclosesPd-catalyzed coupling of CF₃—I with benzene in 26% GC yield.

According to Table 1 entry 10 the coupling of C₆F₁₃I provided 81% yield.But a repetition of this experiment with the bromide instead of theiodide provided less than 1% yield, see Comparative Example 11 herein.

There was a need for homogenous catalyzed method for the preparation offluoro, chloro and fluorochloro alkylated compounds by direct C—Htrifluoromethylation, which provides high yields but does not need theassistance of a directing group or of electron rich aromatic compounds.The method should be applicable to a wide variety of substrates andshould be compatible with a wide variety of functional groups.Furthermore the method should not be restricted to iodides as alkylatingagents only, but should also work with other halides. And the methodshould work not only with perfluorinated alkyl iodides, but also withfluorinated, chlorinated and fluorochlorinated alkyl halides, especiallyfor fluorinated alkyl halides.

Unexpectedly the presence of di(1-adamantyl)-n-butylphosphine and2,2,6,6-tetramethylpiperidine 1-oxyl together with a soluble Pd basedcatalyst meets these requirements. No dialkylated products are observed.

In this text, the following meanings are used, if not otherwise stated:

Ac acetate;

alkyl linear or branched alkyl;

BuPAd₂ CAS 321921-71-5, di(1-adamantyl)-n-butylphosphine;

DMSO dimethylsulfoxide;

eq, equiv equivalent;

halide F—, Cl—, Br— or I—, preferably Cl—, Br—, and I—, more preferablyBr— and I—;

halogen F, Cl, Br or I; preferably F, Cl or Br; more preferably F or Cl;

“linear” and “n-” are used synonymously with respect to the respectiveisomers of alkanes;

MTBE methyl tert-butyl ether;

RT room temperature, it is used synonymously with the expression ambienttemperature;

TEA triethylamine;

TEMPO CAS 2564-83-2,2,2,6,6-tetramethylpiperidine 1-oxyl;

TFA trifluoroacetate;

“wt%”, “% by weight” and “weight-%” are used synonymously and meanpercent by weight.

SUMMARY OF THE INVENTION

Subject of the invention is a method for the preparation of a fluoro,chloro or fluorochloro alkylated compound by a reaction of a compoundCOMPSUBST with a compound FCLALKYLHALIDE by homogeneous catalysis usinga catalyst CAT

in the presence of BuPAd₂ and

in the presence of TEMPO and

in the presence of a compound BAS,

BAS is selected from the group consisting of Cs₂CO₃, CsHCO₃, NEt₃, andmixtures thereof;

FCLALKYLHALIDE is a compound of formula (III):R3—X   (III)

X is Cl, Br or I;

R3 is C₁₋₂₀ alkyl or a C₁₋₂₀ alkyl, wherein in the alkyl chain at leastone of the hydrogens is substituted by F or Cl;

CAT is selected from the group consisting of Pd(OAc)², Pd(TFA)₂, andmixtures thereof;

COMPSUBST is selected from the group consisting of a compoundCOMPSUBST-I, ethene, cyclohexene, ethine, and polystyrene;

-   -   the ethene and the cyclohexene being unsubstituted or        substituted by 1, 2 or 3 substitutents selected from the group        consisting of C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy,        N(R10)R11, CN, NO, NO₂, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1,        S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl, phenyl, naphthyl and        morpholine;    -   the ethine being unsubstituted or substituted by 1 substitutent        selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈        cycloalkyl, C₁₋₄ alkoxy, N(R10)R11, CN, NO, NO_(2,) F, Cl, Br,        I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl,        phenyl and naphthyl;

COMPSUBST-I contains a ring RINGA;

RINGA is an unsaturated or aromatic, 5 or 6 membered carbocyclic orheterocyclic ring,

-   -   when RINGA is a heterocyclic ring, then RINGA has 1, 2 or 3        identical or different endocyclic heteroatoms independently from        each other selected from the group consisting of N, O and S,    -   when RINGA is a 5 membered ring, then RINGA is unsubstituted or        substituted by 1, 2, 3 or 4 identical or different subsitutents,    -   when RINGA is a 6 membered ring then RINGA is unsubstituted or        substituted by 1, 2, 3, 4 or 5 identical or different        subsitutents,    -   any of said subsitutents of RINGA is independently from any        other of said substitutent of RINGA selected from the group        consisting of C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, OH,        N(R10)R11, CN, NH—OH, NO, NO₂, F, Cl, Br, I, CF₃,        (CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl, phenyl        and naphthyl;

RINGA can be condensed with a ring RINGB, RINGB is a 5 or 6 memberedcarbocyclic or heterocyclic ring,

-   -   when RINGB is a heterocyclic ring, is contains 1, 2 or 3        identical or different endocyclic heteroatoms independently from        each other selected from the group consisting of N, O and S;

RINGB is unsubstituted or substituted with 1, 2 or 3 in case of RINGBbeing a 5 membered ring, with 1, 2, 3 or 4 in case of RINGB being a 6membered ring, identical or different substitutents independently fromeach other selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈cycloalkyl, C₁₋₄ alkoxy, OH, N(R17)R18, CN, NH—OH, NO, NO₂, F, Cl, Br,I, CF₃, (CH₂)_(n)—C(O)Y2, S(O)₂R51, CH═C(H)R38, C≡C—R34, benzyl, phenyland naphthyl;

-   -   any of said C₁₋₁₀ alkyl substitutent of RINGA or RINGB is        unsubstituted or substituted with 1, 2, 3, 4 or 5 identical or        different substituents selected from the group consisting of        halogen, OH, O—C(O)—C₁₋₅ alkyl, O—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl,        S(O)—C₁₋₁₀ alkyl, S(O₂)—C₁₋₁₀ alkyl, O—C₁₋₆ alkylen-O—C₁₋₆        alkyl, C₃₋₈ cycloalkyl and 1,2,4-triazolyl;    -   any of said benzyl, phenyl and naphthyl substitutent RINGA or        RINGB is independently from each other unsubstituted or        substituted with 1, 2, 3, 4 or 5 identical or different        substituents selected from the group consisting of halogen, C₁₋₄        alkoxy, NO₂ and CN;        m, n and q are identical or different and independently from        each other 0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10;

Y1, Y2 and R13 are identical or different and independently from eachother selected from the group consisting of H, OH, C(R14)(R15)R16, C₁₋₆alkyl, O—C₁₋₆ alkyl, phenyl, benzyl, O-phenyl, O—C₁₋₆ alkylen-O—C₁₋₆alkyl and N(R19)R20;

R14, R15 and R16 are identical or different and independently from eachother selected from the group consisting of H, F, Cl and Br;

R10, R11, R17, R18, R19 and R20 are identical or different and areindependently from each other H or C₁₋₆ alkyl, or R10 and R11, R17 andR18 or R19 and R20 represent together a tetramethylene or apentamethylene chain;

R50 and R51 are identical or different and independently from each otherselected from the group consisting of OH, C₁₋₆ alkyl and C₁₋₆ alkoxy;

R24, R34, R28 and R38 are identical or different and independently fromeach other selected from the group consisting of H, C₁₋₆ alkyl,C(R25)(R26)—O—R27;

R25, R26 and R27 are identical or different and independently from eachother selected from the group consisting of H and C₁₋₆ alkyl.

DETAILED DESCRIPTION OF THE INVENTION

Preferably, RINGA is a carbocyclic unsaturated ring, a carbocyclicaromatic ring, a heterocyclic unsaturated ring or a heterocyclicaromatic ring.

Preferably, COMPSUBST is selected from the group consisting of compoundCOMPSUBST-I, ethene, cyclohexene, ethine, and polystyrene;

-   -   the ethene and the cyclohexane being unsubstituted or        substituted by 1 or 2 substitutents selected from the group        consisting of C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,        N(R10)R11, CN, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50,        benzyl, phenyl, naphthyl and morpholine;    -   the ethine being unsubstituted or substituted by 1 substitutent        selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₆        cycloalkyl, C₁₋₄ alkoxy, N(R10)R11 , CN, F, Cl, Br, I, CF_(3,)        (CH₂)_(m)—C(O)Y1, S(O)₂R50, benzyl, phenyl and naphthyl;        with COMPSUBST-I being selected from the group consisting of

with COMPSUBST-I being unsubstituted or substituted

-   -   by 1, 2, 3 or 4 in case of COMPSUBST-I being a monocyclic        compound with 5 endocyclic atoms,    -   by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic        compound with 6 endocyclic atoms,    -   by 1, 2, 3, 4, 5 or 6 in case of COMPSUBST-I being a bicyclic        compound wherein a 5-membered and a 6-membered ring are        ortho-fused,    -   by 1, 2, 3, 4, 5, 6 or 7 in case of COMPSUBST-I being a bicyclic        compound wherein two 6-membered rings are ortho-fused,    -   identical or different substituents independently from each        other selected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈        cycloalkyl, C₁₋₄ alkoxy, OH, C(H)═O, N(R10)R11, CN, NH—OH, NO,        NO₂, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28,        C≡C—R24, benzyl, phenyl and naphthyl;        said C₁₋₁₀ alkyl substitutent of COMPSUBST-I is unsubstituted or        substituted with 1, 2, 3, 4 or 5 identical or different        substituents selected from the group consisting of halogen, OH,        O—C(O)—C₁₋₅ alkyl, O—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl, S(O)—C₁₋₁₀        alkyl, S(O₂)—C₁₋₁₀ alkyl, O—C₁₋₆ alkylen-O—C₁₋₆ alkyl, C₃₋₈        cycloalkyl and 1,2,4-triazolyl;        said benzyl, phenyl and naphthyl substitutent of COMPSUBST-I is        independently from each other unsubstituted or substituted with        1, 2, 3, 4 or 5 identical or different substituents selected        from the group consisting of halogen, C₁₋₄ alkoxy, NO₂ and CN;

R10, R11, m, n, Y1, Y2, R28, R50 and R24 are defined as above, also withall their embodiments.

Preferably, m, n and q are identical or different and independently fromeach other 0, 1, 2, 3 or 4:

more preferably, m, n and q are 0 or 4.

In another embodiment, Y1, Y2 and R13 are identical or different andindependently from each other selected from the group consisting of H,OH, C(R14)(R15)R16, C₂₋₆ alkyl, O—C₁₋₆ alkyl, phenyl, benzyl, O-phenyl,O—C₁₋₆ alkylen-O—C₁₋₆ alkyl and N(R19)R20.

Preferably, Y1, Y2 and R13 are identical or different and independentlyfrom each other selected from the group consisting of H, OH, C₁₋₂ alkyl,and O—C₁₋₂ alkyl.

More preferably, COMPSUBST-I is unsubstituted or substituted

-   -   by 1, 2 or 3 in case of COMPSUBST-I being a monocyclic compound        with 5 endocyclic atoms,    -   by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic        compound with 6 endocyclic atoms,    -   by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a bicyclic        compound wherein a 5-membered and a 6-membered ring are        ortho-fused,    -   by 1, 2, 3 or 4 in case of COMPSUBST-I being a bicyclic compound        wherein two 6-membered rings are ortho-fused,    -   identical or different substituents independently from each        other selected from the group consisting of C₁₋₄ alkyl, C₁₋₄        alkoxy, OH, C(H)═O, N(R10)R11, CN, F, Cl, Br, CF₃,        (CH₂)_(m)—C(O)Y1, and S(O)₂R50;        said C₁₋₄ alkyl substitutent of COMPSUBST-I is substituted or        substituted with 1, 2 or 3 identical or different substituents        selected from the group consisting of halogen;        with R10, R11, Y1 and R50 as defined above, also with all their        embodiments.

Especially, COMPSUBST is selected from the group consisting of benzene,pyrazole,

compound of formula (VI), ethene, cyclohexane, ethine, and polystyrene;

Y is C₁₋₆ alkyl;

the ethene and the cyclohexene being unsubstituted or substituted by 1or 2 substitutents selected from the group consisting of C₁₋₁₀ alkyl,C₁₋₄ alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, benzyl,phenyl and morpholine;

the ethine being unsubstituted or substituted by 1 substitutent selectedfrom the group consisting of C₁₋₁₀ alkyl, C₁₋₄ alkoxy, N(R10)R11, CN, F,Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, benzyl and phenyl;

wherein

R44 is selected from the group consisting of C₁₋₁₀ alkyl, C₁₋₄ alkoxy,OH, N(R10)R11, CN, NO, NO₂, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1,S(O)₂R50;

with R10, R11, m, Y1 and R50 as defined above, also with all theirembodiments.

Embodiments of the substituted ethene are propene,ethene-1,1-diyldibenzene and 3,3-dimethylbut-1-ene.

An embodiment of substituted cyclohexene is4-(cyclohex-1-en-1-yl)morpholine.

An embodiment of the substituted ethine is 1-octyne.

Preferably, Y is methyl or ethyl.

An embodiment of COMPSUBST is

Y is methyl or ethyl, preferably ethyl.

The fluoro, chloro or fluorochloro alkylated compound is called compoundALKYLCOMPSUBST.

The fluoro, chloro and fluorochloro alkyl halide is compoundFCLALKYLHALIDE.

Preferably, FCLALKYLHALIDE is a compound of formula (III);R3—X   (III)

X is Cl, Br or I;

R3 is C₁₋₂₀ alkyl or a C₁₋₂₀ alkyl, wherein in the alkyl chain at leastone of the hydrogens is substituted by F or Cl;

more preferably,

R3 is C₁₋₁₅ alkyl, wherein in the alkyl chain at least one of thehydrogens is substituted by F or Cl;

even more preferably,

R3 is C₁₋₁₀ alkyl or C₁₋₁₀ alkyl, wherein in the alkyl chain at leastone of the hydrogens is substituted by F or Cl.

Preferably,

X is Br or I;

more preferably,

X is I;

in another more preferably embodiment,

X is Br;

also with R3 in all its embodiments.

In an especial ambodiment, compound FCLALKYLHADLIDE is a perfluoroalkylhalide, F₂HC—Cl or F₂HC—Br, preferably FCLALKYLHADLIDE is aperfluoroalkylated bromide or iodide, F₂HC—Cl or F₂HC—Br;

preferably

X is Cl, Br or I, and

R3 is perfluoro C₁₋₂₀ alkyl; or

FCLALKYLHADLIDE is F₂HC—Cl or F₂HC—Br;

more preferably,

X is Br or I, and

R3 is perfluoro C₁₋₂₀ alkyl; or

FCLALKYLHADLIDE is F²HC—Cl or F₂HC—Br;

even more preferably,

X is Br or I, and

R3 is perfluoro C₁₋₁₅ alkyl; or

FCLALKYLHADLIDE is F₂HC—Cl or F₂HC—Br.

In particular, FCLALKYLHALIDE is selected from the group consisting ofF₂₁C₁₀—I, F₁₇C₈—I, F₁₃C₆—I, F₉C₄—I, F₃C—I, F₃C—Br, F₃C—Cl, F₂HC—Cl, andF₂HC—Br;

more in particular, FCLALKYLHALIDE is selected from the group consistingof n-F₂₁C₁₀-I, n-F₁₇C₈—I, n-F₁₃C₆—I, n-F₉C₄—I, F₃C—I, F₃C—Br, F₃C—Cl,F₂HC—Cl, and F₂HC—Br.

In one embodiment, the reaction is done in the presence of a compoundCOMPSALT;

COMPSALT is selected from the group consisting of NaI, KI, CsI andN(R30)(R31)(R32)R33I;

R30, R31, R32 and R33 are identical or different and independently fromeach other selected from the group consisting of H and C₁₋₁₀ alkyl;

preferably, R30, R31, R32 and R33 are identical or different andindependently from each other selected from the group consisting of Hand C₂₋₆ alkyl;

more preferably, COMPSALT is selected from the group consisting of NaIand (n-Bu)₄NI.

The reaction is preferably done in the presence of a compound COMPSALTand X is Cl or Br, preferably X is Cl.

Preferably, CAT is Pd(OAc)₂.

Preferably, from 0.1 to 20 mol%, more preferably from 1 to 15 mol%, evenmore preferably from 2.5 to 12.5 mol%, of CAT are used in the reaction,the mol% are based on the molar amount of COMPSUBST.

Preferably, from 1 to 20 mol equivalents, more preferably 1 to 15 molequivalents, even more preferably from 1 to 10 mol equivalents, ofFCLALKYLHALIDE are used in the reaction, the mol equivalents are basedon the molar amount of COMPSUBST.

In case of FCLALKYLHALIDE being in gaseous form, preferablyFCLALKYLHALIDE was used in the reaction in an amount which correspondsto a pressure of from 1 to 10 bar, more preferably from 1 to 5 bar, atambient temperature.

Preferably, from 1 to 40 mol%, more preferably 5 to 30 mol%, even morepreferably from 5 to 25%, of BuPAd₂ are used in the reaction, the mol%are based on the molar amount of COMPSUBST.

Preferably, from 0.1 to 10 mol equivalents, more preferably 0.5 to 5 molequivalents, even more preferably from 0.75 to 2.5 mol equivalents, ofTEMPO are used in the reaction, the mol equivalents are based on themolar amount of COMPSUBST.

Preferably, BAS is Cs₂CO₃.

Preferably, from 0.1 to 10 mol equivalents, more preferably 0.5 to 5 molequivalents, even more preferably from 0.75 to 2.5 mol equivalents, ofBAS are used in the reaction, the mol equivalents are based on the molaramount of COMPSUBST.

The reaction temperature of the reaction is preferably from 20 to 200°C., more preferably from 50 to 200° C., even more preferably from 50 to150° C., especially from 100 to 150° C., more especially from 110 to145° C.

The reaction time of the reaction is preferably from 1 h to 60 h, morepreferably from 10 h to 50 h, even more preferably from 15 h to 50 h.

Preferably, the reaction is done under inert atmosphere. Preferably, theinert atmosphere is achieved by the use if an inert gas preferablyselected from the group consisting of argon, another noble gas, lowerboiling alkane, nitrogen and mixtures thereof.

The lower boiling alkane is preferably a C₁₋₃ alkane, i.e. methane,ethane or propane.

The reaction can be done in a closed system, it can be done at apressure caused by the chosen temperature in a closed system, and/orcaused by the pressure applied by COMPSUBST, in case that COMPSUBST isin gaseous form. It is also possible to apply pressure with said inertgas. It is also possible to carry out the reaction at ambient pressure.

The reaction can be done in a solvent SOL, SOL is preferably selectedfrom the group consisting of alkanes, chlorinated alkanes, ketones,ethers, esters, aliphatic nitrils, aliphatic amides, sulfoxides, andmixtures thereof;

preferably SOL is selected from the group consisting of C₅₋₈ alkane,chlorinated C₅₋₈ alkane, acetone, methylethylketone, diethylketone,MTBE, tetrahydrofuran, methyltetrahydrofuran, ethylacetate,butylacetate, valeronitril, acetonitrile, dimethylformamide,dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide, and mixturesthereof;

more preferably SOL is selected from the group consisting of acetone,methylethylketone, diethylketone, valeronitril, acetonitrile,dimethylsulfoxide, and mixtures thereof;

even more preferably SOL is selected from the group consisting ofacetone, methylethylketone, diethylketone, dimethylsulfoxide, andmixtures thereof.

It is also possible to use COMPSUBST simultaneously as substrate and assolvent.

As an alternative, the reaction can also be carried out in the absenceof a solvent. In another embodiment, COMPSUBST is used as SOL.

The amount of SOL is preferably from 0.1 to 100 fold, more preferablyfrom 1 to 50 fold, even more preferably from 1 to 25 fold, of the weightof COMPSUBST.

After the reaction, ALKYLCOMPSUBST can be isolated by standard methodssuch as evaporation of volatile components, extraction, washing, drying,concentration, crystallization, chromatography and any combinationthereof, which are known per se to the person skilled in the art.

COMPSUBST, BAS, CAT, BuPAd₂, TEMPO and FCLALKYLHALIDE, the fluoro,chloro and fluorochloro alkyl halide, are commercially available and canbe prepared according to known precedures.

EXAMPLES Yield

The yield is given in % as a molar yield of the expected ALKYLCOMPSUBSTin the reaction mixture after the reaction, and is based on molar amountof COMPSUBST and was determined by ¹⁹F NMR with 1,4 difluorobenzene asinternal standard, if not otherwise stated.

Isolated yield was derived from the weight of the isolated product andis based on the weight of COMPSUBST, isolated yield is given inparenthesis in Table 1.

Ratio of Isomers and Position of Alkylation

were determined by NMR spectroscopy

Example 1

An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)₂ (10mol%), BuPAd₂ (20 mol%), TEMPO (1.0 eq), Cs₂CO₃ (2.0 eq), 1, 4dimethoxybenzene (0.2 mmol, 1 eq). Then, acetone (0.5 mL) were injectedinto the vial under argon flow, The vial was placed in an alloy plate,which was transferred into a 300 mL autoclave of the 4560 series fromParr Instruments under an argon atmosphere. A pressure of 3 to 5 barCF₃Br followed by 15 bar of N₂ was adjusted at ambient temperature. Thereaction mixture was stirred at 130° C. for 40 h. After the reaction wasfinished, the autoclave was cooled down to room temperature and thepressure was released.

The reaction mixture was extracted with water and ethyl acetate (5times, each time with 3 mL). The organic layers were washed with brine,dried over Na₂SO₄, and evaporated to yield the crude product. The yieldwas 81 %.

The purification was done by flash chromatography on silica gel (eluent:heptanes:EtOAc=60:40 (v/v)). Isolated yield was 69%.

Details are also given in Table 1

Example 2

Example 1 repeated with the sole difference that Pd(TFA)₂ was used asCAT instead of Pd(OAc)₂. The yield was 78%.

Example 3

Example 1 repeated with the diffenerence that only 5 mol% of Pd(OAc)₂were used instead of 10 mol%, and that only 10 mol% BuPAd₂ were usedinstead of 20 mol%. The yield was 42%.

Example 4

Example 1 repeated with the sole diffenerence that the reaction mixturewas stirred at 130° C. for 30 h instead of 40 h. The yield was 70%.

Examples 5 to 21

Example 1 was repeated with the difference that as COMPSUBST thecompound listed in Table 1 was used.

TABLE 1 Example COMPSUBT ALYKLCOMPSUBST Yield (Ratio of Isomers) 1

(69) 5

(81) 6

(76) (2:1 of a:b) 7

(52) 8

78 (3:1 of a:b) 9

72 10

61 11

25 12

53 13

70 (2:1.2:1 of a:b:c) 14

(47) 15

(79) 16

(76) 17

80 18

(64) 19

20

(61) 21

(48)

Example 22

An oven-dried 4 mL with stir bar was charged with Pd(OAc)₂ (10 mol%),BuPAd₂ (20 mol%), TEMPO (1.0 eq), Cs₂CO₃ (2.0 eq), benzene (0.6 mmol, 1eq) and perfluorohexyl bromide (3.2 eq). Then, acetone (2.5 mL) wereinjected into the vial under argon flow. The vial was placed in an alloyplate, which was transferred into a 300 mL autoclave of the 4560 seriesfrom Parr Instruments under an argon atmosphere. A pressure of 15 bar ofN₂ was adjusted at ambient temperature. The reaction mixture was stirredat 130° C. for 40 h. After the reaction was finished, the autoclave wascooled down to room temperature and the pressure was released.

The reaction mixture was extracted with water and ethyl acetate (5times, each time with 3 mL). The organic layers were washed with brine,dried over Na₂SO₄, and evaporated to yield the crude product. Thereaction mixture was analyzed by ¹⁹F-NMR by which an yield of 21%(perfluorohexyl)benzene was found. The identity of the(perfluorohexyl)benzene was confirmed by GC-MS.

A repetition of the experiment provided 28% yield with a conversion of35%.

Example 23

An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)₂ (10%),BuPAd₂ (20 mol%), TEMPO (1.0 eq), CsCO₃ (2.0 eq), 1,4-dimethoxybenzene(0.2 mmol, 1 eq) and perfluorohexyl bromide (3.2 eq). Then, acetone (1mL) were injected into the vial under argon flow. The vial was placed inan alloy plate, which was transferred into a 300 mL autoclave of the4560 series from Parr Instruments under an argon atmosphere. A pressureof 15 bar of N₂ was adjusted at ambient temperature. The reactionmixture was stirred at 130° C. for 40 h.

After the reaction was finished, the autoclave was cooled down to roomtemperature and the pressure was released.

The reaction mixture was extracted with water and ethyl acetate (5times, each time with 3 mL). The organic layers were washed with brine,dried over Na₂SO₄, and evaporated to yield the crude product. Thereaction mixture was analyzed by GC—MS by which an yield of 42%1,4-dimethoxy-2-(perfluorohexy)benzene was found.

Example 24

An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)₂ (10mol%), BuPAd₂ (20 mol%), TEMPO (1.0 eq), Cs₂CO₃ (2.0 eq),ethene-1,1-diyldibenzene (0.5 mmol, 1 eq) Then, acetone (2 mL) wereinjected into the vial under argon flow. The vial was placed in an alloyplate, which was transferred into a 300 mL autoclave of the 4560 seriesfrom Parr Instruments under an argon atmosphere. A pressure of 3 to 5bar CF₃Br followed by 15 bar of N₂ was adjusted at ambient temperature.The reaction mixture was stirred at 130° C. for 40 h. After the reactionwas finished, the autoclave was cooled down to room temperature and thepressure was released.

The reaction mixture was filtered and the filter residue was washed withethylacetate and acetone. The combined filtrates were concentrated on arotary evaporator. The residue was purified by column chromatography onsilica gel (eluent: heptanes:EtOAc=90:10 (v/v)). Isolated yield was 58%.

¹H NMR Analysis of the obtained product showed a 2:1 mixture of(3,3,3-trifluoroprop-1-ene-1,1-diyl) dibenzene and(3,3,3-trifluoropropane-1,1-diyl)dibenzene. The identities of(3,3,3-trifluoroprop-1-ene-1,1-diyl)dibenzene and(3,3,3-trifluoropropane-1,1-diyl)dibenzene were confirmed by GC-MS.

Examples (Ex) 25 and 26 and Comparative Examples (CompEx) 1 to 10

Standard Procedure:

An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)₂ (10mol%), BuPAd₂ (20 mol%), ADDITIVE (1.0 eq), BASE (2.0 eq) and 1,4dimethoxybenzene (0.2 mmol, 1 eq). Then, SOLVENT (0.5 mL) was injectedinto the vial under argon flow. The vial was placed in an alloy plate,which was transferred into a 300 mL autoclave of the 4560 series fromParr Instruments under an argon atmosphere. A pressure of 3 to 5 barCF₃Br followed by 15 bar of N₂ was adjusted at ambient temperature. Thereaction mixture was stirred at 130° C. for 40 h.

After the reaction was finished, the autoclave was cooled down to roomtemperature and the pressure was released.

The reaction mixture was extracted with water and ethyl acetate (5times, each time with 3 mL). The organic layers were washed with brine,dried over Na₂SO₄, and evaporated to yield the crude product. The yieldof the product was determined by ¹⁹F-NMR spectroscopy.

In CompEx 4 Pd(TFA)₂ was used as CAT instead of Pd(OAc)₂.

Table 2 shows the parameters that were tested.

TABLE 2 YIELD ADDITIVE BASE SOLVENT (¹⁹F-NMR) CompEx 1 1,4-BenzoquinoneCs₂CO₃ Acetone 38% CompEx 2 Pivalic acid Cs₂CO₃ Acetone 31% CompEx 3Ag₂O Cs₂CO₃ Acetone 23% CompEx 4 TEMPO K₂CO₃ Acetone 35% CompEx 5 TEMPONa₂CO₃ Acetone 42% Ex 25 TEMPO TEA Acetone 51% CompEx 6 TEMPO CsIAcetone 14% CompEx 7 TEMPO CsF Acetone 26% CompEx 8 TEMPO NaI Acetone19% CompEx 9 TEMPO K₃PO₄ Acetone 4% CompEx 10 TEMPO K-tert. Acetone 39%butoxide Ex 26 TEMPO Cs₂CO₃ DMSO 74%

Example 27

An oven-dried 4 mL vial with stir bar was charged with Pd(OAc)₂ (10mol%), BuPAd₂ (20 mol%), TEMPO (1 eq), Cs₂CO₃ (2.0 eq) and ethylacrylate (0.5 mmol, 1 eq). Then, acetone (0.5 mL) were injected into thevial under argon flow sequentially. The vial was placed in an alloyplate, which was transferred into a 300 mL autoclave of the 4560 seriesfrom Parr Instruments under an argon atmosphere. A pressure of 3 to 5bar CF₃Br followed by 15 bar of N₂ was adjusted at ambient temperature.The reaction mixture was stirred at 130° C. for 40 h.

After the reaction was finished, the autoclave was cooled down to roomtemperature and the pressure was released.

The resulting reaction mixture was cooled, the pressure released fromthe autoclave, and the solids filtered. The filtered reaction mixturewas analyzed by ¹⁹F-NMR using the internal standard 1,4-difluorobenzeneshowing an yield of 26% of ethyl-4,4,4-trifluorobut-2-enoat (delta¹⁹F-NMR: −65.68 ppm (d, J=9.5 Hz)). GC-MS Analysis showed a molecularweight peak at 168 g/mol confirming monotrifluormethylation.

Comparative Example 11

The entry 10 in Table 1 of Loy, R. N., et al., Organic Letters 2011, 13,2548-2551, was repeated according to the detailed procedure given in theSupporting Information for said article, which is described under“Optimization procedure” on page S3 in connection with entry 9 in TableS4 on page S5.

The phosphine was BINAP.

[Pd] was Pd₂dba3.

The base was Cs₂CO₃.

The alkylhalogenid was perfluorohexyl bromide instead of perfluorohexyliodide.

To a screw cap 1 dram vial was added base (0.4 mmol, 2 equiv), [Pd](0.02 mmol, 10 mol%) and phosphine (0.04-0.08 mmol, 20-40 mol%). Benzene(1 mL) and perfluorohexyl bromide (43 microL, 0.2 mmol, 1 equiv) wereadded, and the resulting mixture was sealed with a Teflon-lined cap andheated in an aluminum reaction block with a vigorous stirring for 15 hat 80° C. The reaction mixture was cooled to 23° C. and chlorobenzene(20 microL) was added as a GC internal standard. An aliquot (˜100microL) was removed from the crude reaction mixture and passed through aplug of Celite, eluting with EtOAc (2 mL). This sample was then analyzedby GC, and the yield was determined by comparison to a calibrationagainst the chlorobenzene internal standard.

Result

A yield of less than 1% was measured.

Example 28

A dried 50 mL autoclave was charged with4-(cyclohex-1-en-1-yl)morpholine (0.2 mmol), Pd(OAc)₂ (10 mol%), BuPAd₂(20 mol%), TEMPO (1.0), Cs₂CO₃ (2.0 equivalents). Then, acetone (2 mL)was injected into the autoclave and the autoclave was flushed with argonfor 3 times. A pressure of 6 bar CF₃Br followed by 15 bar of N₂ wasadjusted at ambient temperature. The reaction mixture was heated at 130°C. for 40 h. The autoclave was placed in a heating system and heated at130° C. for 40 h. After the completion of the reaction, the autoclavewas cooled down to room temperature and the pressure was released. 20micdoL of 1,2 difluorobenzene (internal standard) was added to thereaction mixture and a sample was submitted for ¹⁹F NMR. The yield wasmeasured by ¹⁹F NMR. The NMR data is in accordance with the literatureN. V. Kirij et al., Journal of Fluorine Chemistry, 2000, 106, 217 to221.

The invention claimed is:
 1. A method for the preparation of a fluoro,chloro or fluorochloro alkylated compound by a reaction of a compoundCOMPSUBST with a compound FCLALKYLHALIDE by homogeneous catalysis usinga catalyst CAT in the presence of BuPAd₂ and in the presence of TEMPOand in the presence of a compound BAS, BAS is selected from the groupconsisting of Cs₂CO₃, CsHCO₃, NEt₃, and mixtures thereof; FCLALKYLHALIDEis a compound of formula (III);R3—X   (III) X is Cl, Br or I; R3 is C₁₋₂₀ alkyl or a C₁₋₂₀ alkyl,wherein in the alkyl chain at least one of the hydrogens is substitutedby F or Cl; CAT is selected from the group consisting of Pd(OAc)₂,Pd(TFA)₂, and mixtures thereof; COMPSUBST is selected from the groupconsisting of a compound COMPSUBST-I, ethene, cyclohexene, ethine, andpolystyrene; the ethene and the cyclohexene being unsubstituted orsubstituted by 1, 2 or 3 substituents selected from the group consistingof C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, N(R10)R11, CN, NO, NO₂, F,Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl,phenyl, naphthyl and morpholine; the ethine being unsubstituted orsubstituted by 1 substituent selected from the group consisting of C₁₋₁₀alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, N(R10)R11, CN, NO, NO₂, F, Cl, Br,I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl, phenyland naphthyl; COMPSUBST-1 contains a ring RINGA; RINGA is an unsaturatedor aromatic, 5 or 6 membered carbocyclic or heterocyclic ring, whenRINGA is a heterocyclic ring, then RINGA has 1, 2 or 3 identical ordifferent endocyclic heteroatoms independently from each other selectedfrom the group consisting of N, O and S, when RINGA is a 5 memberedring, then RINGA is unsubstituted or substituted by 1, 2, 3 or 4identical or different substituents, when RINGA is a 6 membered ringthen RINGA is unsubstituted or substituted by 1, 2, 3, 4 or 5 identicalor different substituents, any of said substituents of RINGA isindependently from any other of said substituent of RINGA selected fromthe group consisting of C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄ alkoxy, OH,N(R10)R11, CN, NH—OH, NO, NO₂, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1,S(O)₂R50, CH═C(H)R28, C═C—R24, benzyl, phenyl and naphthyl; RINGA can becondensed with a ring RINGB, RINGB is a 5 or 6 membered carbocyclic orheterocyclic ring, when RINGB is a heterocyclic ring, is contains 1, 2or 3 identical or different endocyclic heteroatoms independently fromeach other selected from the group consisting of N, O and S; RINGB isunsubstituted or substituted with 1, 2 or 3 in case of RINGB being a 5membered ring, with 1, 2, 3 or 4 in case of RINGB being a 6 memberedring, identical or different substituents independently from each otherselected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄alkoxy, OH, N(R17)R18, CN, NH—OH, NO, NO₂, F, Cl, Br, I, CF₃,(CH₂)_(n)—C(O)Y2, S(O)₂R51, CH═C(H)R38, C≡C-R34 benzyl, phenyl andnaphthyl; any of said C₁₋₁₀ alkyl substituent of RINGA or RINGB isunsubstituted or substituted with 1, 2, 3, 4 or 5 identical or differentsubstituents selected from the group consisting of halogen, OH,O—C(O)—C₁₋₅ alkyl, O—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl, S(O)—C₁₋₁₀ alkyl,S(O₂)-C₁₋₁₀ alkyl, O—C₁₋₆ alkylen-O—C₁₋₆ alkyl, C₃₋₈ cycloalkyl and1,2,4-triazolyl; any of said benzyl, phenyl and naphthyl substituent ofRINGA or RINGB is independently from each other unsubstituted orsubstituted with 1, 2, 3, 4 or 5 identical or different substituentsselected from the group consisting of halogen, C₁₋₄ alkoxy, NO₂ and CN;m, n and q are identical or different and independently from each other0, 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10; Y1, Y2 and R13 are identical ordifferent and independently from each other selected from the groupconsisting of H, OH, C(R14)(R15)R16, C₁₋₆ alkyl, O—C₁₋₆ alkyl, phenyl,benzyl, O-phenyl, O—C₁₋₆ alkylen-O—C₁₋₆ alkyl and N(R19)R20; R14, R15and R16 are identical or different and independently from each otherselected from the group consisting of H, F, Cl and Br; R10, R11, R17,R18, R19 and R20 are identical or different and are independently fromeach other H or C₁₋₆ alkyl, or R10 and R11, R17 and R18 or R19 and R20represent together a tetramethylene or a pentamethylene chain; R50 andR51 are identical or different and independently from each otherselected from the group consisting of OH, C₁₋₆ alkyl and C₁₋₆ alkoxy;R24, R34, R28 and R38 are identical or different and independently fromeach other selected from the group consisting of H, C₁₋₁₀ alkyl,C(R25)(R26)—O—R27; R25, R26 and R27 are identical or different andindependently from each other selected from the group consisting of Hand C₁₋₁₀ alkyl.
 2. The method according to claim 1, wherein COMPSUBSTis selected from the group consisting of compound COMPSUBST-I, ethene,cyclohexene, ethine, and polystyrene; the ethene and the cyclohexenebeing unsubstituted or substituted by 1 or 2 substituents selected fromthe group consisting of C₁₋₁₀ alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy,N(R10)R11, CN, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1, S(O)₂R50, benzyl,phenyl, naphthyl and morpholine; the ethine being unsubstituted orsubstituted by 1 substituent selected from the group consisting of C₁₋₁₀alkyl, C₃₋₆ cycloalkyl, C₁₋₄ alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF₃,(CH₂)_(m)—C(O)Y1, S(O)₂R50, benzyl, phenyl and naphthyl; withCOMPSUBST-I being selected from the group consisting of

with COMPSUBST-I being unsubstituted or substituted by 1, 2, 3 or 4 incase of COMPSUBST-I being a monocyclic compound with 5 endocyclic atoms,by 1, 2, 3, 4 or 5 in case of COMPSUBST-I being a monocyclic compoundwith 6 endocyclic atoms, by 1, 2, 3, 4, 5 or 6 in case of COMPSUBST-Ibeing a bicyclic compound wherein a 5-membered and a 6-membered ring areortho-fused, by 1, 2, 3, 4, 5, 6 or 7 in case of COMPSUBST-I being abicyclic compound wherein two 6-membered rings are ortho-fused,identical or different substituents independently from each otherselected from the group consisting of C₁₋₁₀ alkyl, C₃₋₈ cycloalkyl, C₁₋₄alkoxy, OH, C(H)═O, N(R10)R11, CN, NH—OH, NO, NO₂, F, Cl, Br, I, CF₃,(CH₂)_(m)—C(O)Y1, S(O)₂R50, CH═C(H)R28, C≡C—R24, benzyl, phenyl andnaphthyl; said C₁₋₁₀ alkyl substituent of COMPSUBST-I is unsubstitutedor substituted with 1, 2, 3, 4 or 5 identical or different substituentsselected from the group consisting of halogen, OH, O—C(O)—C₁₋₅ alkyl,O—C₁₋₁₀ alkyl, S—C₁₋₁₀ alkyl, S(O)—C₁₋₁₀ alkyl, S(O₂)—C₁₋₁₀ alkyl,O—C₁₋₆ alkylen-O—C₁₋₆ alkyl, C₃₋₈ cycloalkyl and 1,2,4-triazolyl; saidbenzyl, phenyl and naphthyl substituent of COMPSUBST-I is independentlyfrom each other unsubstituted or substituted with 1, 2, 3, 4 or 5identical or different substituents selected from the group consistingof halogen, C₁₋₄ alkoxy, NO₂ and CN.
 3. The method according to claim 1,wherein m, n and q are identical or different and independently fromeach other 0, 1, 2, 3 or
 4. 4. The method according to claim 1, whereinCOMPSUBST is selected from the group consisting of benzene, pyrazole,

compound of formula (VI), ethene, cyclohexene, ethine, and polystyrene;Y is C₁₋₆ alkyl; the ethene and the cyclohexene being unsubstituted orsubstituted by 1 or 2 substituents selected from the group consisting ofC₁₋₁₀ alkyl, C₁₋₄ alkoxy, N(R10)R11, CN, F, Cl, Br, I, CF₃,(CH₂)_(m)—C(O)Y1, benzyl, phenyl and morpholine; the ethine beingunsubstituted or substituted by 1 substituent selected from the groupconsisting of C₁₋₁₀ alkyl, C₁₋₄ alkoxy, N(R10)R11, CN, F, Cl, Br, I,CF₃, (CH₂)_(m)—C(O)Y1, benzyl and phenyl;

wherein R44 is selected from the group consisting of C₁₋₁₀ alkyl, C₁₋₄alkoxy, OH, N(R10)R11, CN, NO, NO₂, F, Cl, Br, I, CF₃, (CH₂)_(m)—C(O)Y1,S(O)₂R50.
 5. The method according to claim 1, wherein X is Br or I. 6.The method according to claim 1, wherein X is Br.
 7. The methodaccording to claim 1, wherein compound FCLALKYLHADLIDE is aperfluoroalkyl halide, F₂HC—Cl or F₂HC—Br.
 8. The method according toclaim 1, wherein X is Cl, Br or I, and R3 is perfluoro C₁₋₂₀ alkyl, orFCLALKYLHADLIDE is F₂HC—Cl or F₂HC—Br.
 9. The method according to claim1, wherein FCLALKYLHALIDE is selected from the group consisting ofF₂₁C₁₀—I, F₁₇C₈—I, F₁₃C₆—I, F₉C₄—I, F₃C—I, F₃C—Br, F₃C—Cl, F₂HC—Cl, andF₂HC—Br.
 10. The method according to claim 1, wherein the reaction isdone in the presence of a compound COMPSALT; COMPSALT is selected fromthe group consisting of NaI, KI, CsI and N(R30)(R31)(R32)R33I; R30, R31,R32 and R33 are identical or different and independently from each otherselected from the group consisting of H and C₁₋₁₀ alkyl.
 11. The methodaccording to claim 10, wherein R30, R31, R32 and R33 are identical ordifferent and independently from each other selected from the groupconsisting of H and C₂₋₆ alkyl.
 12. The method according to claim 10,wherein COMPSALT is selected from the group consisting of NaI and(n-Bu)₄NI.
 13. The method according to claim 1, wherein CAT is Pd(OAc)₂.